Genetic Variants Associated with HDL and LDL Cholesterol, and Triglyceride Levels

高水平的低密度脂蛋白(ldl-c)和低水平的高密度脂蛋白(hdl-c)是独立的危险因素。 冠心病(CAD)的致病因素。在该奖项的指导阶段，我们确定了59个 与血脂水平相关的新区域(Teslovich等人，2010年)。我们正在继续我们的研究以确定 通过几种策略与血脂水平相关的新基因和遗传区域，其中几种是 本奖项指导阶段的成功AIMS的延期。我们将继续测试 通过测试100,000个额外的 样本。我们还参与了NHLBI的外显子组测序项目的分析，该项目已经 完成了417个样本的完整外显子测序，这些样本都来自低密度脂蛋白上或下1%的尾部 分发。识别新的、高度破坏性的基因突变可能提供关于 在一个潜在的大区域中，哪个基因可能参与脂肪代谢，典型的 识别包含相关孟德尔基因罕见破坏性突变的基因常见变异的范例 精神错乱。对于该奖项的独立阶段，设计的实验旨在了解功能 将进行先前已确定的遗传信号的基础工作，包括对发挥作用的遗传变异进行比对 公开可获得的芯片序列中已知转录因子结合位点的位置对血脂水平的影响 数据。该奖项独立阶段的最终目标是利用来自1000个基因组的信息 对大约1000万个与血脂水平相关的SNP进行归因和测试的项目，将相关变异编目在 相关区域和完善远程调控元素的签名。

High levels of LDL cholesterol (LDL-c) and low levels of HDL cholesterol (HDL-c) are independent risk factors for coronary artery disease (CAD). During the mentored phase of this award, we have identified 59 novel regions associated with lipid levels (Teslovich et al., 2010). We are continuing our research to identify novel genes and genetic regions associated with lipid levels through several strategies, several of which are extensions to successful aims from the Mentored Phase of this award. We will continue to test for association in a GWAS framework by testing the most promising 5,000 genetic variants in 100,000 additional samples. We are also involved in the analysis ofthe Exome Sequencing Project of NHLBI which has completed whole exome sequencing of 417 samples, all from the upper or lower 1% tails ofthe LDL-c distribution. Identification of novel, highly disruptive genetic mutations may provide valuable clues about which gene in a potentially large region may be involved in lipid metabolism, a reversal of the typical paradigm to identify common variants in genes that contain rare disruptive mutations for related Mendelian disorders. For the independent phase of this award, experiments designed to understand the functional basis of previously identified genetic signals will be undertaken, including aligning genetic variants that play a role in lipid levels with position of known transcription factor binding sites from publicly-available Chip-Seq data. The final aim for the independent phase ofthe award is to use information from the 1000 Genomes Project to impute and test ~10 million SNPs for association with lipid levels, catalog associated variants in associated regions and refine signatures of long-range regulatory elements.